The present invention relates to novel spiro compounds or salts thereof that inhibit the activity of a transcription factor AP-1 and are useful as agents for treating autoimmune diseases, agents for preventing and/or treating autoimmune diseases and an AP-1 inhibitor containing the same.
Up to today, therapeutic drugs for many diseases have been developed to control the functions of proteins such as enzymes and receptors. For example, for treating inflammatory diseases such as rheumatoid arthritis, etc., cycloxygenase synthesizing prostaglandins from arachidonic acid or 5-lipoxygenase synthesizing leucotrienes have been taken as a target, and a number of non-steroidal antiinflammatory drugs such as indomethacin have been developed and put to therapeutic uses (J. Pharm. Sci., Vol. 73, Pages 579-589, 1984). Inflammatory cytokines such as interleukins (IL)-1 and IL-6 and tumor necrotic factor (TNF) have attracted intention as amplifying or aggravating factors in inflammatory reaction. As agents for regulating the functions of these proteins, monoclonal antibodies for respective proteins (Arthritis Rheum., Vol. 36, Pages 1681-1690, 1993), low molecular weight cytokine production inhibitors (Ann. Rep. Med. Chem., Vol. 27, Pages 209-218, 1992), etc. are being developed. Further, the use of antibodies for those cytokine receptors is also being attempted clinically (Rheumatism, Vol. 37, No. 2, Page 174, 1997).
In the diseases caused by a quantitative abnormality of functional proteins existing in cells or on cell membranes or of functional molecules secreted from cells, however, it is considered that a therapy in the true sense is to regulate the quantity of transcription of functional molecule gene and thereby normalize the quantity of expression rather than to inhibit the activity of the functional molecules. It is known that not only the quantitative abnormalities of the above-mentioned inflammatory cytokines and lipid mediators synthesized from arachidonic acid but also the quantitative abnormalities of many functional proteins such as adhesion molecules and matrix metallo proteinases take part in the cause of autoimmune diseases such as rheumatoid arthritis and chronic inflammatory diseases (N. Engl. J. Med., Vol. 322, Pages 1277-1289, 1990). Although gene expression and production of these functional proteins are regulated by a plurality of transcription factors, it is known that the promoter region of a majority of such genes commonly involves a consensus sequences of transcription factor AP-1 (TRE sequence). Further, it has been reported that expression of some of these functional proteins is regulated by binding of AP-1 to the promoter region (Nature, Vol. 337, Pages 661-663, 1989).
A living body exhibits various defensive reactions against outer stimulation and attack, and shows immune responses and inflammatory reactions.
Cellular and molecular analyses of such reactions have made a surprising progress in the recent years, due to which it has become apparent that gene expression and production of proteins to make sure the physiological functions was induced the stimulation in all the cells constituting a living body.
The immune responses and inflammatory reactions are amplified and regulated by the interaction of these genes including inflammatory cytokines such as IL-1 and TNFxcex1, cell surface molecules such as cell-adhesion molecules and various cytokine receptors and enzymes such as matrix metallo-proteinases. On the other hand, autoimmune diseases typified by rheumatoid arthritis and other intractable chronic inflammatory diseases are considered caused by an excessive immunity and inflammatory reactions. That is, it is prospected that, in these inflammatory diseases, such a wide variety of genes directly relating to the etiology of disease are expressed in an excessive quantity, so that a mere inhibition or control of only one genetic product (protein) is incapable of realizing a sufficient therapy (radical therapy).
At the present time, non-steroidal anti-inflammatory agents and steroidal agents are used for the pharmaceutical treatment of chronic inflammatory diseases such as rheumatoid arthritis. Non-steroidal anti-inflammatory agents such as indomethacin and the like inhibit cycloxygenase and thereby suppress the production of lipid mediators such as prostaglandin E2 and the like. However, such a treatment is not sufficient as a radical therapy because the use of these drugs is to suppress only one inflammatory mediator, cycloxygenase, and the effect thereof is nothing but an expectation of a conservative treatment. On the other hand, steroidal agents are known to exhibit regulating effect at the stage of expression of gene through intermediation of a glucocorticoid receptor, and it has actually been reported that these agents inhibit the activity of transcription factor AP-1 and thereby suppress the production of cytokines and other proteins (Cell, Vol. 62, Pages 1189-1204, 1990). Although effectiveness of such steroidal agents are sufficiently recognized, the use of such steroidal agents is restricted by the hormonal and side effects thereof, and they cannot be administered over a long period of time. Especially, the inflammatory diseases such as autoimmune diseases are generally chronic and require a long-term therapy, so that drugs having intense side effects cannot be used at least at the present time.
Thus, it has been desired to develop an agent for treating and/or preventing autoimmune diseases which inhibits AP-1 activity and can suppress the expression of a wide variety of genes through inhibiting AP-1 activity thereof, with lessened side reactions.
The present inventors have conducted extensive studies with the aim of developing an agent for treating and/or preventing autoimmune diseases which inhibits AP-1 activity and can suppress the expression of a wide variety of genes through inhibiting AP-1 activity thereof, with lessened side reactions. As a result, it has been found-that spiro compounds having a spiro ring skeleton represented by the following general formula [1]: 
wherein A is a group of the following general formula: 
wherein R1a represents hydrogen atom, halogen atom, cyano group, nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; and Y0 represents oxygen atom, sulfur atom, an unsubstituted or substituted imino group, carbonyl group, methylene group, vinylene group, sulfinyl group, sulfonyl group or group xe2x80x94CH(OH)xe2x80x94; or a group of the following general formula: 
wherein R1c and R1d, same or different, each represents hydrogen atom, halogen atom, cyano group, nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group;
or a group of the following general formula: 
wherein R1e and R1f, same or different, each represents halogen atom, cyano group, nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; or a group of the following general formula: 
wherein R1g represents an unsubstituted or substituted heterocyclic group;
R2 represents hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, acyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R3 and R4, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R3 and R4, taken conjointly, represent an oxo group; R5 and R6, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R5 and R6, taken conjointly with the terminal carbon atom to which R5 and R6 are combined, represent an alkenyl group; and n represents 0, 1 or 2;
spiro compounds represented by the general formula [1] wherein A is a group represented by the following general formula: 
wherein R1h represents a group of the following general formula:
R11xe2x80x94Y2xe2x80x94
wherein R11 represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl, hydroxyl or mercapto group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamoyl, carbamoyloxy or heterocyclic group; and Y2 represents methylene group, an unsubstituted or substituted imino group, carbonyl group or sulfonyl group; or a group of the following general formula:
R12xe2x80x94(E1)jxe2x80x94
wherein E1 represents amino acid residue; R12 represents hydrogen atom or a protecting group for amino group; and j represents 2 or 3;
R2 represents hydrogen atom, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, acyl, aryl, arylsulfonyl, alkylsulfonyl, aralkyl or heterocyclic group;
R3 and R4, taken conjointly, represent an oxo group; R5 represents hydrogen atom; R6 represents a group of the following general formula: 
wherein R13 represents hydrogen atom, halogen atom, an unprotected or protected hydroxyl, hydroxyamino, amino, alkylamino, arylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino or alkylsulfonylamino group, an unsubstituted or substituted alkyl, aryloxy, aralkyloxy, alkylthio, alkoxy, aryl or heterocyclic group, or a group of the following general formula:
R14xe2x80x94(E2)lxe2x80x94
wherein E2 represents amino acid residue; R14 represents hydroxyl group or amino group; and l represents 1, 2 or 3; k represents 1, 2 or 3; and n represents 0, 1 or 2;
spiro compounds represented by general formula [1] wherein A represents a group of the following general formula: 
wherein R1h represents a group of the following general formula:
R15xe2x80x94Y3xe2x80x94
wherein R15 represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl, hydroxyl or mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamoyl, carbamoyloxy or heterocyclic group; and Y3 represents methylene group, an unsubstituted or substituted imino group, carbonyl group or sulfonyl group; or
a group of the following general formula:
R16xe2x80x94(E3)sxe2x80x94
wherein E3 represents amino acid residue; R16 represents hydrogen atom or a protecting group for amino group; and s represents 2 or 3;
R2 represents hydrogen atom, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, acyl, aryl, arylsulfonyl, alkylsulfonyl, aralkyl or heterocyclic group; R3 and R4, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group; or a group of the following general formula:
xe2x80x94COxe2x80x94(E4)txe2x80x94R18
wherein E4 represents amino acid residue; R18 represents hydroxyl group or amino group; and t represents 1, 2 or 3; R5 and R6, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group; and n represents 0, 1 or 2; and salts of the above-mentioned spiro compounds inhibit the activity of transcription factor AP-1 and are useful as an agent for preventing and/or treating autoimmune diseases. Based on this finding, the present invention has been accomplished.
The compounds of the present invention inhibit the activity of transcription factor AP-1. That is to say, the compound of the present invention inhibits the transcription of DNAs having a TRE alignment in the promoter region thereof. Thereby, it is possible to inhibit the production of proteins corresponding to the gene in genes having TRE sequence. Accordingly, the compounds of the present invention can suppress the expression of genes of cytokines group such as IL-1xcex2, IL-2, IL-3, IL-8, TNFxcex1, granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP-1), etc., MMPs such as collagenase (MMP-1), stromelycin (MMP-3), collagenase IV (MMP-9), etc., cell surface molecules such as immunoglobulins, major histocompatibility complex (MHC) class II, vascular cell adhesion molecule 1 (VCAM-1), fibroblast growth factor (FGF) receptor, etc., growth factors such as monocyte growth factor, insulin-related growth factor (IGF), nerve growth factor (NGF), etc., and metallothionein, collagen, osteocarcin, osteopontin, amyloid precursor protein, apolipoprotein-1, etc. Accordingly, the compounds of the present invention can prevent and/or treat the diseases is related to these genes.
As the diseases is related these genes, for example, collagen diseases (rheumatoid arthritis, systemiclupus erythematosus, general scleroderma, rheumatic fever, multiple myositis, periarteritis nodosa, Sjxc3x6gren""s syndrome and Behxc3xa7et""s syndrome), idiopathic ulcerative colitis, glomerulonephritis, various autoimmune diseases such as autoimmune hemolytic anemia and the like, active chronic hepatitis, osteoarthritis, gout, atherosclerosis, psoriasis, atopic dermatitis, lungal diseases accompanied by granuloma such as interstitial pneumonia, various meningitises, Alzheimer""s disease, and other intractable chronic inflammatory diseases can be referred to.
Hereunder, the compounds of the present invention will be detailed.
Unless otherwise referred to, the term xe2x80x9chalogen atomxe2x80x9d used in this specification means fluorine atom, chlorine atom, bromine atom and iodine atom; the term xe2x80x9calkyl groupxe2x80x9d means a straight or branched chain C1-12 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; the term xe2x80x9calkenyl groupxe2x80x9d means a straight or branched chain C2-12 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl and the like; the term xe2x80x9ccycloalkyl groupxe2x80x9d means a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; the term xe2x80x9caryl groupxe2x80x9d means a group such as phenyl, tolyl, naphthyl and the like; the term xe2x80x9calkoxy groupxe2x80x9d means a straight or branched chain C1-12 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like; the term xe2x80x9calkoxyimino groupxe2x80x9d means a straight or branched chain C1-12 alkoxyimino group such as methoxyimino, ethoxyimino and the like; the term xe2x80x9calkoxycarbonylamino groupxe2x80x9d means a straight or branched chain C1-12 alkoxycarbonylamino group such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino, sec-butoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino, heptyloxycarbonylamino, octyloxycarbonylamino and the like; the term xe2x80x9carylsulfonylamino groupxe2x80x9d means an aryl-SO2NHxe2x80x94 group such as phenylsulfonylamino, naphthylsulfonylamino and the like; the term xe2x80x9calkylsulfonylamino groupxe2x80x9d means a straight or branched chain C1-12 alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, heptyl-sulfonylamino, octylsulfonylamino and the like; the term xe2x80x9caryloxy groupxe2x80x9d means a group represented by aryl-Oxe2x80x94 such as phenoxy, tolyloxy, naphthoxy and the like; the term xe2x80x9caryloxycarbonyl groupxe2x80x9d means a group represented by aryl-Oxe2x80x94COxe2x80x94 such as phenoxycarbonyl, naphthoxycarbonyl and the like; the term xe2x80x9carylamino groupxe2x80x9d means a group such as phenylamino, naphthylamino and the like; the term xe2x80x9calkylamino groupxe2x80x9d means a mono- or di-C1-12 alkylamino group such as methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, octylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, diheptylamino, dioctylamino and the like; the term xe2x80x9caralkyl groupxe2x80x9d means an ar-C1-12-alkyl group such as benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl and the like; the term xe2x80x9calkylidene groupxe2x80x9d means a C1-12 alkylidene group such as methylene, ethylidene, propylidene, isopropylidene, butylidene, hexylidene, octylidene and the like; the term xe2x80x9caralkyloxy groupxe2x80x9d means an ar-C1-12-alkyloxy group such as benzyloxy, phenethyloxy, 4-methylbenzyloxy, naphthylmethyloxy and the like; the term xe2x80x9caralkyloxycarbonyl groupxe2x80x9d means an ar-C1-12-alkyloxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, 4-methylbenzyloxycarbonyl, naphthylmethyloxycarbonyl and the like; the term xe2x80x9caralkylcarbonyloxy groupxe2x80x9d means an ar-C1-12-alkylcarbonyloxy group such as benzylcarbonyloxy, phenethylcarbonyloxy, 4-methylbenzylcarbonyloxy, naphthylmethylcarbonyloxy and the like; the term xe2x80x9caralkylcarbonyl groupxe2x80x9d means a group represented by aralkyl-COxe2x80x94 wherein aralkyl is as defined above; the term xe2x80x9cacyl groupxe2x80x9d means acyl groups including C2-12 alkanoyl groups such as formyl, acetyl, propionyl and the like, aralkylcarbonyl groups such as benzylcarbonyl and the like, aroyl groups such as benzoyl, naphthoyl and the like and heterocycle-carbonyl groups such as nicotinoyl, thenoyl, pyrrolidinocarbonyl, furoyl and the like; the term xe2x80x9cacyloxy groupxe2x80x9d means a group represented by acyl-Oxe2x80x94 wherein acyl is as defined above; the term xe2x80x9cacylamino groupxe2x80x9d means a C1-6 acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino and the like; the term xe2x80x9caralkyloxycarbonyl groupxe2x80x9d means an ar-C1-12-alkyloxy-COxe2x80x94 group such as benzyloxycarbonyl, phenethyloxycarbonyl, 4-methylbenzyloxycarbonyl, naphthylmethyloxycarbonyl and the like; the term xe2x80x9ccyclic amino groupxe2x80x9d means a cyclic amino group which may be any of saturated and unsaturated cyclic amino groups and may contain at least one heteroatom such as nitrogen atom, oxygen atom, sulfur atom or the like and a carbonyl carbon in the ring thereof and may be any of monocyclic, bicyclic and tricyclic amino groups, of which more specific examples include saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups containing one nitrogen atom such as aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl, piperidino, dihydroazepin-1-yl, perhydroazepin-1-yl and the like; saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups containing two nitrogen atoms such as imidazol-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, 1,4-dihydropyrazin-1-yl, 1,2-dihydropyrimidin-1-yl, perhydropyrazin-1-yl, homopiperazin-1-yl and the like; saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups containing three or more nitrogen atoms such as 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, 1,2-dihydro-1,2,4-triazin-1-yl, perhydro-S-triazin-1-yl and the like; saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups containing 1 to 4 heteroatoms selected from the group consisting of oxygen atom and sulfur atom in addition to nitrogen atom such as oxazolidin-3-yl, isoxazolidin-2-yl, morpholino, 1,3-oxazolidin-3-yl, thiazolidin-1-yl, isothiazolidin-1-yl, thiomorpholino, homothiomorpholin-1-yl, 1,2,4-thiadiazolin-2-yl and the like; saturated or unsaturated, bicyclic or tricyclic cyclic amino groups such as isoindolin-2-yl, indolin-1-yl, 1H-indazol-1-yl, purin-7-yl, tetrahydroquinolin-1-yl and the like; and spiro or crosslinked, saturated or unsaturated, 5- to 12-membered cyclic amino groups such as 5-azaspiro[2,4]heptan-5-yl, 2,8-diazabicyclo[4.3.0]-nonan-8-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 2-oxa-5,8-diazabicyclo[4.3.0]nonan-8-yl, 2,8-diazaspiro[4,4]-nonan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl and the like; the term xe2x80x9cheterocyclic groupxe2x80x9d means a 4- to 7-membered or fused heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom such as azetidinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiazidiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiatriazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, 1,2,4-triazinyl, benzothienyl, naphthothienyl, benzofuryl, isobenzofuryl, chromenyl, indolidinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, triazolopyridyl, tetrazolopyridazinyl, tetrazolopyrimidinyl, thiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, benzothiazolyl, 1,2,3,4-tetrahydroquinolyl, imidazo[1,2-b][1,2,4]triazinyl, quinuclidinyl and the like; the term xe2x80x9calkanoyl groupxe2x80x9d means a C2-12 alkanoyl group such as acetyl, propionyl and the like; the term xe2x80x9caroyl groupxe2x80x9d means an aroyl group such as benzoyl, naphthoyl and the like; the term xe2x80x9cheterocycle-carbonyl groupxe2x80x9d means a group represented by heterocycle-COxe2x80x94 wherein heterocycle is as defined above); the term xe2x80x9calkylthio groupxe2x80x9d means a straight or branched chain C1-12 alkylthio group such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio and the like; the term xe2x80x9calkylsulfinyl groupxe2x80x9d means a straight or branched chain C1-12 alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl, heptylsulfinyl, octylsulfinyl and the like; the term xe2x80x9calkylsulfonyl groupxe2x80x9d means a straight or branched chain C1-12 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl and the like; the term xe2x80x9carylsulfonyl groupxe2x80x9d means, for example, phenylsulfonyl group or naphthylsulfonyl group; the term xe2x80x9calkylsulfonyloxy groupxe2x80x9d means a straight or branched chain C1-12 alkylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, hexylsulfonyloxy, heptylsulfonyloxy, octylsulfonyloxy and the like; the term xe2x80x9carylsulfonyloxy groupxe2x80x9d means a group such as phenylsulfonyloxy, naphthylsulfonyloxy and the like; the term xe2x80x9calkoxycarbonyl groupxe2x80x9d means a straight or branched chain C1-12 alkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like; and the term xe2x80x9calkoxycarbonyloxy groupxe2x80x9d means a straight or branched chain C1-12 alkyloxycarbonyloxy group such as methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy and the like.
As R1a, R1b, R1c, R1d, R1e, R1f, R1g, R1aa, R1ba, R1ca, R1da, R1ea, R1fa, R1la, Raa, Rbb, Rcc, Rdd, Ree, Rff, Raaa, Rbbb, Rccc, Rddd, Reee, Rfff, R2, R2a, R3, R4, R5, R6, R11, R13, R13a, R13aa, R15, R15a, Y, Y0, Y2, Y3 and the substituents used in the formulas of production processes, for example, halogen atom, cyano group, nitro group, sulfo group, mercapto group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl and hydroxyimino groups, an unprotected or protected amino group, an unprotected or protected imino group, an unsubstituted or substituted alkyl, alkoxy, alkoxycarbonyl, alkoxyimino, acyl, acyloxy, carbamoyl, carbamoyloxy, aralkylcarbonyloxy, aryl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyl, alkenyl, aralkyl, alkylthio, alkylsulfonyl, alkylsulfonyloxy, alkylidene and heterocyclic groups, an unprotected or protected cyclic amino, aminosulfonyl, aminosulfinyl, alkoxycarbonylamino and alkylamino groups can be referred to. If desired, these groups may be substituted with at least one of these substituents. As the substituted alkyl group in R1b, R1ba, Rbb and Rbbb, the same groups as above can be referred to, and they are substituted with at least one of these substituents.
The protecting groups for carboxyl group which can be used include all the groups conventionally usable as a protecting group for carboxyl group. As examples thereof, there can be referred to alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl, n-butyl, tert-butyl and the like; aryl groups such as phenyl, naphthyl and the like; aralkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl and the like; acyl-alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like; halogeno-alkyl groups such as 2,2,2-trichloroethyl and the like; alkylsilylalkyl groups such as 2-(trimethylsilyl)ethyl and the like; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and the like; nitrogen-containing heterocycle-alkyl groups such as phthalimidomethyl, succinimidomethyl and the like; cycloalkyl groups such as cyclohexyl and the like; alkoxy-alkyl groups such as methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl and the like; ar-alkoxy-alkyl groups such as benzyloxymethyl and the like; alkylthio-alkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; arylthio-alkyl groups such as phenylthiomethyl and the like; alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.
The protecting groups for amino group which can be used include all the groups conventionally usable as a protecting group for amino group. As examples thereof, there can be referred to acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylcarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like; aralkyl groups such as benzyl, diphenylmethyl, trityl and the like; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthio and the like; alkyl- and aryl-sulfonyl groups such as methanesulfonyl, paratoluenesulfonyl and the like; dialkylamino-alkylidene groups such as N,N-dimethylaminomethylene and the like; aralkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene and the like; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclohexylidene and the like; diaryl- and diaralkylphosphoryl groups such as diphenylphosphoryl, dibenzylphosphoryl and the like; oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl and the like; and substituted silyl groups such as trimethylsilyl and the like.
The protecting groups for hydroxyl group which can be used include all the groups conventionally usable as a protecting group for hydroxyl group. As examples thereof, there can be referred to acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)-ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenyloxyacetyl, pivaloyl, benzoyl and the like; alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl and the like; alkenyl groups such as allyl and the like; aralkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; alkoxy-alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl and the like; alkyl- and aryl-sulfonyl groups such as methanesulfonyl, paratoluenesulfonyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.
The term xe2x80x9camino acid residuexe2x80x9d means an xe2x80x94NH(CHR)ZCOxe2x80x94 part (R is an amino acid side chain, and Z is an integer of 1 to 6) which appears when an amino acid is introduced into a protein molecule or a peptide molecule while forming a peptide bonding with loss of a water molecule. Herein, the term xe2x80x9camino acidxe2x80x9d means a compound having a carboxyl group and an amino group in one molecule such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, asparagine, aspartic acid, glutamine, glutamic acid, lysine, alginine, histidine, methionine, thyrosine, phenylalanine, tryptophane, proline, cysteine, homocysteine, xcex2-alanine, xcex3-aminobutyric acid, ornithine, 3,4-dihydroxyphenylalanine and the like.
As the salt of the compound of general formula [1], usually known salts formed at the site of basic group such as amino group and the like and at the site of acidic group such as hydroxyl or carboxyl group and the like can be referred to. As the salt formed at the site of a basic group, for example, salts of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts of an organic acid such as tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts of a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like can be referred to. As the salts formed at the site of an acid group, for example, salts of alkali metals such as sodium, potassium and the like; salts of alkaline earth metals such as calcium, magnesium and the like; ammonium salts; and salts of nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-xcex2-phenethylamine, 1-ephenamine, and N,Nxe2x80x2-dibenzylethylene-diamine and the like can be referred to. Of the salts mentioned above, preferred salts of the compound of general formula [1] are pharmacologically acceptable ones.
Among the compounds of the present invention, preferred are the compounds in which A represents a group of the following general formula: 
wherein Raaa represents hydrogen atom, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, acyl, alkoxycarbonyl, amino or heterocyclic group; and Yaaa represents oxygen atom, sulfur atom, carbonyl group, vinylene group, sulfinyl group or sulfonyl group; a group of the following general formula: 
wherein Rbbb represents an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, substituted alkyl group or an unsubstituted or substituted alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, acyl, alkoxycarbonyl, amino or heterocyclic group; a group of the following general formula: 
wherein Rccc and Rddd, same or different, each represents hydrogen atom, an unprotected or protected carboxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, acyl, alkoxycarbonyl, amino or heterocyclic group; or a group of the following general formula: 
wherein Reee and Rfff, same or different, each represents an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, acyl, alkoxycarbonyl, amino or heterocyclic group; R2 represents hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, acyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R3 and R4, same or different, each represents hydrogen atom, an unprotected or protected carboxyl group or an unsubstituted or substituted alkyl, acyl, alkoxycarbonyl, carbamoyl group or a group of the following general formula:
xe2x80x94(CH2)mxe2x80x94COxe2x80x94(D)pxe2x80x94R7
wherein D represents amino acid residue; R7 represents hydroxyl group or amino group; p represents 1, 2 or 3; and m represents 0, 1, 2 or 3, or R3 and R4, taken conjointly, represent an oxo group; R5 and R6, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or R5 and R6, taken conjointly with the terminal carbon atom to which R5 and R6 are combined, represent an alkenyl group; and n represents 0, 1 or 2.
Also, preferred are the compounds in which A represents a group of the following general formula: 
wherein R1ha represents a group of the following general formula:
R11axe2x80x94Y2axe2x80x94
wherein R11a represents an unsubstituted or substituted alkyl, alkenyl, aryl, alkoxy or heterocyclic group; and Y2a represents methylene group, carbonyl group or sulfonyl group; or a group represented by the following general formula:
R12xe2x80x94(E1)jxe2x80x94
wherein E1 represents amino acid residue; R12 represents hydrogen atom or a protecting group for amino group; and j represents 2 or 3; R2 represents hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, aryl, aralkyl or heterocyclic group; R6 represents a group of the following general formula: 
wherein R13aa represents an unprotected or protected hydroxyl, amino, alkylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino or alkylsulfonylamino group or an unsubstituted or substituted alkyl or alkoxy group; and k represents 1, 2 or 3; or a group of the following general formula:
R14axe2x80x94(E2)jxe2x80x94
wherein E2 represents amino acid residue; R14a represents hydroxyl group or amino group; and j represents 1, 2 or 3.
Also, preferred are the compounds in which A represents a group of the following general formula: 
wherein R1hb represents a group of the following general formula:
R15axe2x80x94Y3axe2x80x94
wherein R15a represents an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; and Y3a represents carbonyl group or a group of the following general formula:
R16axe2x80x94(E3a)s0xe2x80x94
wherein E3a represents amino acid residue; R16a represents hydrogen atom or a protecting group for amino group; and s0 represents 2 or 3; R2 represents hydrogen atom or an unsubstituted or substituted acyl group; R3 represents hydrogen atom; R4 represents carbamoyl group or a group of the following general formula:
xe2x80x94COxe2x80x94(E4a)t0xe2x80x94R18a
wherein E4a represents amino acid residue; R18a represents hydroxyl group or amino group; and t0 represents 1, 2 or 3; R5 and R6, same or different, each represents hydrogen atom, an unsubstituted or substituted alkyl group; and n represents 0.
Among the compounds of the present invention, further preferred are the compounds in which A represents a group of the following general formula: 
wherein Raa represents an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; and Yaa represents oxygen atom or vinylene group; a group of the following general formula: 
wherein Rbb represents an unsubstituted or substituted alkyl group or an unsubstituted or substituted alkenyl, aryl or heterocyclic group; a group of the following general formula: 
wherein Rcc and Rdd, same or different, each represents hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; or a group of the following general formula: 
wherein Ree and Rff, same or different, each represents an unprotected or protected hydroxyl group or an unsubstituted or substituted aryl group; R2 represents hydrogen atom, formyl group, alkanoyl group, aralkylcarbonyl group or an unsubstituted or substituted alkyl, alkenyl, aroyl, heterocycle-carbonyl, aryl, aralkyl or heterocyclic group; R3 and R4, same or different, each represents hydrogen atom, an unsubstituted or substituted alkoxycarbonyl, carbamoyl group or a group of the following general formula:
xe2x80x94(CH2)mxe2x80x94COxe2x80x94(D)pxe2x80x94R7
wherein D represents amino acid residue; R7 represents hydroxyl group or amino group; p represents 1, 2 or 3; and m represents 0, 1, 2 or 3, or R3 and R4, taken conjointly, represent an oxo group; R5 and R6, same or different, each represents hydrogen atom or an unsubstituted or substituted alkyl group; and n represents 0 or 2.
Also, further preferred are the compounds in which A represents a group of the following general formula: 
wherein R1ha represents a group of the following general formula:
R11axe2x80x94Y2axe2x80x94
wherein R11a represents an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; and Y2a represents methylene group, carbonyl group or sulfonyl group; R2 represents hydrogen atom or an unsubstituted or substituted alkyl or aralkyl group; R6 represents a group of the following general formula: 
wherein R13a represents an unprotected or protected hydroxyl, amino, alkylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino or alkylsulfonylamino group or an unsubstituted or substituted alkoxy group; and k0 represents 1; and n represents 0.
As representative examples of the compound of the present invention, the compounds of the following Tables 1 to 51 can be referred to.
Some of the compounds of the present invention represented by general formula [1] or salts thereof have isomers such as optical isomers, geometrical isomers and tautomers. In such cases, the present invention involves such isomers. Further, the present invention involves solvated products, hydrated products and a variety of crystal forms.
Next, the process for producing the compounds of the present invention will be described.
The compounds of the present invention can be synthesized according to, for example, the Production Processes 1 and 2 mentioned below.
[Production Process 1]
[Production Process 2]
wherein R2, R3, R4, R5, R6 and A are as defined above; R2a represents an unsubstituted or substituted acyl or sulfonyl group; Rxe2x80x2 represents an unsubstituted or substituted alkyl or aryl group; Rxe2x80x3 represents tert-butyl group or trichloroethyl group; R8 and R9, same or different, each represents hydrogen atom or an unsubstituted or substituted alkyl, aryl or heterocyclic group; R10 represents an unsubstituted or substituted amino group, nxe2x80x2 represents 1 or 2; and Z represents halogen atom, alkylsulfonyloxy group or arylsulfonyloxy group.
[Production Process 1]
Next, the process for producing the compounds of the present invention will be described.
The compounds of the present invention can be produced by combining the processes which are known in themselves, namely, according to the production processes mentioned below, for example.
The compound of the general formula [1a] can be produced by, for example, the process mentioned in Yakugaku Zasshi, Vol. 91, No, 3, Pages 363-383 (1971), or the like. More concretely speaking, the compounds of the present invention can be obtained by reacting a compound of general formula [2] with an amine represented by general formula [3] or an ammonium salt and a compound represented by general formula [4] in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the reaction product to a dehydrating ring closure.
As the amines which can be used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine or the like and amino acids such as leucine, asparagine, aspartic acid, xcex2-alanine or the like can be referred to. As the ammonium salts, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine of general formula [3] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. The compound of general formula [4] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent which can be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [2]. As the catalyst which can be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C. for a period of 30 minutes to 24 hours.
The compound of general formula [1b] can be obtained, for example, according to the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [2] with an amine represented by general formula [3] or an ammonium salt and a compound represented by general formula [5] which can be synthesized according to the method described in SYNTHETIC COMMUNICATIONS, Vol. 21, No. 2, Pages 249-263 (1991) or the like in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the reaction product to a dehydrating ring closure. As the amines which can be used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine and the like, amino acids such as leucine, asparagine, aspartic acid, xcex2-alanine and the like, etc. can be referred to. As the ammonium salts, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine represented by general formula [3] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. The compound of general formula [5] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent, for example, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be used in an amount of 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [2]. As the catalyst which may be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C. for a period of 30 minutes to 24 hours.
The compound of general formula [1c] can be obtained, for example, according to the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [2] with an amine represented by general formula [3] or an ammonium salt and mercaptoacetic acid in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the reaction product to a dehydrating ring closure. As the amines which can be used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine and the like, amino acids such as leucine, asparagine, aspartic acid, xcex2-alanine and the like, etc. can be referred to. As the ammonium salts, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine represented by general formula [3] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. The mercaptoacetic acid is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent which may be used according to the need, for example, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be used in an amount of 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [2]. As the catalyst which may be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
The compound of general formula [1b] can be obtained by, for example, reacting a compound of general formula [1c] with a compound of general formula [6] in the presence of a base. As the base used in this reaction, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-5 mol per mol of the compound of general formula [1c]. The compound of general formula [6] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [1c]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at xe2x88x9278xc2x0 C. to 150xc2x0 C. and preferably at xe2x88x9250xc2x0 C. to 120xc2x0 C., for a period of 30 minutes to 24 hours. If desired, the reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
The compound of general formula [1d] can be obtained by reacting a compound of general formula [1c] with an aldehyde or a ketone represented by general formula [7] in the presence or absence of an acid or a base.
As the acid which may be used in this reaction according to the need, for example, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to. The amount thereof is 1-10 mol per mol of the compound of general formula [1c]. As the base which may be used according to the need, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-10 mol per mol of the compound of general formula [1c]. The compound of general formula [7] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [1c]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at xe2x88x9278xc2x0 C. to 150xc2x0 C. and preferably at xe2x88x9250xc2x0 C. to 120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1a] can be obtained by, for example, subjecting a compound of general formula [1b] to a de-esterification reaction in the presence or absence of an acid or a base. As the acid which may be used in this reaction according to the need, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoro-acetic acid, paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [1b]. As the base which may be used according to the need, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [1b].
The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; acetic acid; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1e] can be obtained by, for example, oxidizing a compound of general formula [1a]. As the oxidant which can be used in this reaction, for example, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like; hydrogen peroxide; chromic acid; potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1a]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at a temperature ranging from 0xc2x0 C. to reflux temperature of the used solvent and preferably at 0-30xc2x0 C., for a period of 30 minutes to 24 hours.
[Production Process 2]
The compound of general formula [1f] can be obtained by, for example, the process mentioned in JP-A 53-44574, or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [2] with a compound of general formula [8] in the presence or absence of a base, a dehydrating agent and a catalyst, and subjecting the product to a dehydrating ring closure. Although the compound of general formula [8] used in this reaction is not particularly critical, D-cysteine, L-cysteine, D-penicillamine and L-penicillamine of which C-terminal may optionally be protected and salts thereof can be referred to, for example. The compound of general formula [8] is used in an amount of 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the base which may be used according to the need, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc. can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent which may be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 (w/w) times as much as the amount of the compound of general formula [2]. As the catalyst which may be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-1 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 20-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1g] can be obtained by, for example, subjecting a compound of general formula [1] to an acylation reaction or a sulfonylation reaction in the presence or absence of a base. As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, pyrrolecarbonyl chloride, thiazolecarbonyl chloride and the like can be referred to. As the sulfonylating agent, methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to. The amounts of said acylating agent and sulfonylating agent are 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1]. As the base which may be used according to the need, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1f].
The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1h] can be obtained by, for example, oxidizing a compound of general formula [1g]. As the oxidant which can be used in this reaction, for example, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like, hydrogen peroxide, chromic acid, potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1g]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature ranging from 0xc2x0 C. to the reflux temperature of the used solvent and preferably at 0-30xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1i] can be obtained by, for example, subjecting a compound of general formula [1g] to an amidation reaction.
This reaction is a usual amidation reaction, which can be carried out by, for example, a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. In a case of using a base, a condensing agent and an additive, the amines which can be used in the reaction include primary amines such as methylamine, benzylamine, aniline, phenethylamine, aminothiazole and the like; secondary amines such as dimethylamine, diethylamine, di-n-propylamine and the like; cyclic amines such as piperidine, morpholine and the like; amino acids such as leucine, asparagine, aspartic acid, xcex2-alanine, methionine and the like; and esters thereof. The amine is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1g]. As the base which can be use in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorphline and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1g]. As the condensing agent, dicyclohexyl-carbodiimide, diisopropyl-carbodiimide, N-ethyl-Nxe2x80x2-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to, and as the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The amounts of the condensing agent and the additive are both 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1g]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of [1j] can be obtained by, for example, oxidizing a compound of general formula [1i].
As the oxidant which can be used in this reaction, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like; hydrogen peroxide; chromic acid and potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1i]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature ranging from 0xc2x0 C. to the reflux temperature of the used solvent and preferably at 0-30xc2x0 C., for a period of 30 minutes to 24 hours.
Furthermore, it is also possible to synthesize the compounds of the present invention according to the Production Processes 1a and 2a described below.
[Production Process 1a]
wherein
A is as defined above; Rxe2x80x2 represents an unsubstituted or substituted alkyl or aryl group; Rxe2x80x3 represents tert-butyl group; Rxe2x80x2xe2x80x3 represents an unprotected or protected amino, hydroxyamino, alkylamino, arylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino, alkylsulfonylamino or a group of the following general formula:
xe2x80x94(E2)qxe2x80x2xe2x80x94R13xe2x80x2
wherein E2 represents amino acid residue; and R13xe2x80x2 represents an unprotected or protected hydroxyl, amino, alkylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino, alkylsulfonylamino, or an unsubstituted or substituted alkyl or alkoxy group; and qxe2x80x2 represents 1, 2 or 3; and r represents 0, 1 or 2.
The compound of general formula [1k] can be obtained by, for example, the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [2] with an amine represented by general formula [23] and mercaptosuccinic acid in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the product to a dehydrating ring closure.
As the amine which can be used in this reaction, glycine tert-butyl ester, xcex2-alanine tert-butyl ester and the like can be referred to. The amine of general formula [23] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. The mercaptosuccinic acid is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent which may be used according to the need, for example, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the amount of the compound of general formula [2]. As the catalyst which may be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1l] can be obtained by subjecting a compound of general formula [1k] to an esterification reaction.
This reaction may be practiced according to the usual methods of esterification, such as the method via an acid chloride, the method via an acid anhydride, the method using a base and an alkyl halide, the method of using a condensing agent and an additive, etc. In the case of using a base and an alkyl halide, the base which can be used include organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc. The amount of the base is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. As the alkyl halide which can be used in this reaction, methyl iodide, ethyl iodide, benzyl bromide and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. The reaction is carried out usually at 0-200xc2x0 C. and preferably at 25-150xc2x0 C., for a period of 10 minutes to 24 hours. In the case of using a condensing agent and an additive, the objective compound can be obtained by subjecting an alcohol such as ethanol, benzyl alcohol or the like to a condensation reaction with a condensing agent and an additive. As the condensing agent used in this reaction, for example, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-Nxe2x80x2-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to. As the additive used in this reaction, for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The alcohol, condensing agent and additive used in this reaction are used each in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. The reaction is carried out usually at 0-200xc2x0 C. and preferably at 25-150xc2x0 C., for a period of 10 minutes to 24 hours.
The compound of general formula [1m] can be obtained by, for example, subjecting a compound of general formula [1l] to a de-esterification reaction in the presence of an acid. As the acid which can be used in this reaction according to the need, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to. The amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [1l]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; acetic acid; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1la] can be obtained by, for example, subjecting a compound of general formula [1k] to an amidation reaction.
This reaction is a usual amidation reaction, which can be carried out by, for example, a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. In the case of using a base, a condensing agent and an additive, the amines which can be used in the reaction include primary amines such as methylamine, benzylamine, aniline, phenethylamine, aminothiazole and the like; secondary amines such as dimethylamine, diethylamine, di-n-propylamine and the like; cyclic amines such as piperidine, morpholine and the like; amino acids such as leucine, asparagine, aspartic acid, xcex2-alanine, methionine and the like; compounds prepared by substituting the C-terminal carboxyl group may be substituted of the above-mentioned amino acids with an an unsubstituted or substituted alkyloxycarbonyl or carbamoyl group; compounds prepared by condensing 2 or 3 amino acids such as alanylalanine, leucylalanine or the like of which C-terminal carboxyl group may be substituted with an unsubstituted or substituted alkyloxycarbonyl or carbamoyl group; and the like. The amine is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. As the base which can be use in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorphline and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. As the condensing agent, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-Nxe2x80x2-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to, and as the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The amounts of the condensing agent and the additive are both 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1ma] can be obtained by, for example, subjecting a compound of general formula [1la] to a de-esterification reaction in the presence of an acid. As the acid which may be used in this reaction according to the need, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of the general formula [1la]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; acetic acid; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C., for a period of 30 minutes to 24 hours.
[Production Process 2a]
[Production Process 2b]
wherein R3, R4, R5 and R6 are as defined above; R3a and R4a, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R3a and R4a, taken conjointly, represent an oxo group; R5a and R6a, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R5a and R6a, taken conjointly with the terminal carbon atom to which R5a and R6a are combined, represent an alkenyl group; R3b and R4b, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R3b and R4b, taken conjointly, represent an oxo group; R5b and R6b, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R5b and R6b, taken conjointly with the terminal carbon atom to which R5b and R6b are combined, represent an alkenyl group; R2a represents an unsubstituted or substituted acyl or sulfonyl group; Ra represents hydrogen atom, halogen atom, cyano group, nitro group, protected carboxyl group, protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; Rb and Rbxe2x80x2, same or different, each represents hydrogen atom, halogen atom, cyano group, nitro group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl or alkoxy group, protected amino group, or an unprotected or protected carboxyl group; X0 represents chlorine, bromine or iodine atom; and Rc represents an unsubstituted or substituted alkyl, alkenyl, cycloalkyl or aryl group.
The compound of general formula [24] can be obtained by, for example, according to the method described in JP-A 53-44574, or the like. More concretely speaking, it can be obtained by reacting a compound [12] with a compound of general formula [8] in the presence or absence of a base and a dehydrating agent and subjecting the product to a dehydrating ring closure. Although the compound of general formula [8] which can be used in this reaction is not particularly critical, D-cysteine, L-cycteine, D-penicillamine and L-penicillamine of which C-terminal may optionally be protected and salts thereof can be referred to, for example. The compound of general formula [8] is used in an amount of 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [12]. As the base which may be used according to the need, for example, organic amines such as dimethylaminopyridine, triethyamine, pyridine and the like; and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [12]. As the dehydrating agent which may be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [12]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150xc2x0 C. and preferably at 20-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [25] can be obtained by, for example, subjecting a compound of general formula [24] to an acylation reaction or sulfonylation reaction in the presence or absence of a base. As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, pyrrole carbonyl chloride, thiazole carbonyl chloride and the like can be referred to. As the sulfonylating agent, methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [24]. As the base which may be used according to the need, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like; and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [24].
The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [26] can be obtained by de-protecting a compound of general formula [25] in the presence of an acid. As the acid which can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like, and organic acids such as paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 5-20 mol per mol of the compound of general formula [25]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1o] can be obtained by reacting a compound of general formula [26a] with Wittig reagent or Honer Wadsworth Emmons reagent.
More concretely speaking, the compound of general formula [1o] can be obtained by reacting a compound of general formula [26a] with Wittig reagent which can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Pages 751-754 (1973) or Honer Wadsworth Emmons reagent which can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Pages 509-513 (1973). The Wittig reagent and the Honer Wadsworth Emmons reagent are used in an amount of 0.5-5 mol and preferably 1-2 mol per mol of the compound of general formula [26a]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9278xc2x0 C. to 120xc2x0 C. and preferably at xe2x88x9220xc2x0 C. to 30xc2x0 C., for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
The compound of general formula [1p] can be obtained by, for example, subjecting a compound of general formula [26a] and a compound of general formula [14] to Grignard reaction. The Grignard reagent used in this reaction can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Page 226 (1955). Examples of the Grignard reagent include alkylmagnesium halides such as methylmagnesium bromide and the like and arylmagnesium halides such as phenylmagnesium bromide and the like.
In this reaction, the compound of general formula [14] is used in an amount of 0.5-5 mol and preferably 0.8-2 mol per mol of the compound of general formula [26a].
The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 120xc2x0 C. and preferably at 0-70xc2x0 C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
The compound of general formula [1q] can be obtained by reacting a compound of general formula [26b] with a reductant in the presence or absence of a salt. As the salt which may be used according to the need, lithium chloride, magnesium chloride, calcium chloride and the like can be referred to, and the amount thereof is 1-10 mol per mol of the compound of general formula [26b]. As the reductant, sodium boron hydride, lithium boron hydride, aluminum diisobutyl hydride and the like can be referred to, and the amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [26b]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like; ethers such as tetrahydrofuran, diethyl ether and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; aromatic hydrocarbons such as toluene, benzene, xylene and the like; aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; dimethyl sulfoxide, N,N-dimethylformamide, pyridine, water and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature ranging from xe2x88x9278xc2x0 C. to the reflux temperature of the used solvent and preferably at xe2x88x9278xc2x0 C. to 30xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1r] can be obtained by subjecting a compound of general formula [9] and a compound of general formula [1q] to a Mitsunobu reaction.
This reaction is carried out by using, for example, an azodicarbonyl compound such as diethylazo dicarboxylate, azodicarbonyl dipiperidine or the like and a triaryl phosphine such as triphenyl phosphine or the like or a trialkylphosphine such as tri-n-butyl phosphine or the like. The compound of general formula [9] is used in an amount of 1-5 mol and preferably 1-3 mol per mol of the compound of general formula [1q].
The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 120xc2x0 C. and preferably at 0xc2x0 C. to 30xc2x0 C., for a period of 30 minutes to 24 hours.
The compounds of general formulas [1a], [1b], [1c], [1d], [1e], [1f], [1g], [1h], [1i], [1j], [1k], [1l], [1la], [1m], [1ma], [1o], [1p], [1q] and [1r] which have been obtained in the above-mentioned manner can be converted to other compounds of general formula [1] by, for example, subjecting them to reactions known in themselves such as oxidation, reduction, rearrangement, substitution, halogenation, dehydration, hydrolysis, etc. or appropriately combining these reactions. The compounds of general formula [1] or salts thereof thus obtained can be isolated and purified by the conventional procedures such as extraction, crystallization and/or column chromatography, etc.
Next, the process for producing the compound of general formula [2] which is a starting material for producing the compound of the present invention will be described. The compound of general formula [2] can be obtained by, for example, the following processes.
[Production Process A]
[Production Process B]
[Production Process C]
[Production Process D]
[Production Process E]
wherein Ra represents hydrogen atom, halogen atom, cyano group, nitro group, protected carboxyl group, protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; Rb and Rbxe2x80x2, same or different, each represents hydrogen atom, halogen atom, cyano group, nitro group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl or alkoxy group, protected amino group or an unprotected or protected carboxyl group; Rc represents an unsubstituted or substituted alkyl, alkenyl, cycloalkyl or aryl group; X0 represents chlorine, bromine or iodine atom; Rd and Re represent hydrogen atom, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl or aralkyl group; and Rf and Rg represent a protecting group for carboxyl group.
[Production Process A]
The compound of general formula [11] can be obtained by subjecting a compound of general formula [9] and a compound of general formula [10] to a Mitsunobu reaction.
This reaction can be carried out by, for example, using an azodicarbonyl compound such as diethylazo dicarboxylate, azodicarbonyl dipiperidine or the like and a triaryl phosphine such as triphenyl phosphine or the like or a trialkyl phosphine such as tri-n-butyl phosphine or the like. The compound of general formula [9] is used in an amount of 1-5 mol and preferably 1-3 mol per mol of the compound of general formula [10].
The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 120xc2x0 C. and preferably at 0xc2x0 C. to 30xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [2a] can be obtained by, for example, de-protecting a compound of general formula [11] in the presence of an acid. As the acid which can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; and organic acids such as paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 5-20 mol per mol of the compound of general formula [11]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C., for a period of 30 minutes to 24 hours.
[Production Process B]
The compound of general formula [13] is obtained by reacting a compound of general formula [12] with Wittig reagent or Honer Wadsworth Emmons reagent.
More concretely speaking, the compound of formula [13] can be obtained by reacting a compound of general formula [12] with Wittig reagent which can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Pages 751-754 (1973) or Honer Wadsworth Emmons reagent which can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Pages 509-513 (1973). The Wittig reagent and the Honer Wadsworth Emmons reagent are used in an amount of 0.5-5 mol and preferably 1-2 mol per mol of the compound of general formula [12]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9278xc2x0 C. to 120xc2x0 C. and preferably at xe2x88x9220xc2x0 C. to 30xc2x0 C., for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
The compound of general formula [2b] can be obtained by, for example, de-protecting a compound of general formula [13] in the presence of an acid.
As the acid which can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like, and organic acids such as paratoluenesulfonic acid, methanesulfonic acid and the like can be referred, and the amount thereof is 1-50 mol and preferably 5-20 mol per mol of the compound of general formula [13]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C., for a period of 30 minutes to 24 hours.
[Production Process C]
The compound of general formula [16] can be obtained by, for example, subjecting a compound of general formula [12] and a compound of general formula [14] to Grignard reaction. The Grignard reagent used in this reaction can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Page 226 (1955). Examples of the Grignard reagent include alkylmagnesium halides such as methylmagnesium bromide and the like and arylmagnesium halides such as phenylmagnesium bromide and the like.
In this reaction, the compound of general formula [14] is used in an amount of 0.5-5 mol and preferably 0.8-2 mol per mol of the compound of general formula [12].
The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 120xc2x0 C. and preferably at 0-70xc2x0 C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
The compound of general formula [2c] can be obtained by, for example, de-protecting a compound of general formula [16] in the presence of an acid. As the acid which can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like, and organic acids such as paratoluenesulfonic acid, methanesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 5-20 mol per mol of the compound of general formula [16]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C., for a period of 30 minutes to 24 hours.
[Production Process D]
The compound of general formula [19] can be obtained by, for example, the process mentioned in J. Org. Chem., Vol. 45, Pages 5399-5400 (1980), etc. More concretely speaking, it can be obtained by subjecting a compound of general formula [17] and a compound of general formula [18] to Robinson cyclization reaction. The compound of general formula [18] is used in an amount of 1-10 mol and preferably 2-4 mol per mol of the compound of general formula [17].
The reagent used in this reaction is, for example, an aldehyde such as isobutylaldehyde, cyclohexylaldehyde, 2-phenylpropionaldehyde and the like and a ketone such as methyl vinyl ketone, 3-penten-2-one and the like. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [2d] can be obtained by, for example, reducing a compound of general formula [19]. This reaction may be carried out according to the conventional method for reducing carbon-carbon double bonds, for example, by the method of catalytic reduction using palladium-carbon, Raney nickel or platinum catalyst.
In the case of using a palladium-carbon catalyst, the catalyst is used in an amount of 0.01-1 time (w/w) and preferably 0.05-0.2 time (w/w) as much as the amount of the compound of general formula [19]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; water; acetic acid, etc. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 120xc2x0 C. under normal pressure or elevated pressure, and preferably at 25-50xc2x0 C., for a period of 30 minutes to 24 hours.
[Production Process E]
It is also possible to obtain the compound of general formula [21] according to the method mentioned in SYNTHETIC COMMUNICATIONS, Vol. 15, Pages 141-149 (1985). More concretely speaking, it can be obtained by subjecting a compound of general formula [20] and twice or more molar quantity, per mol of compound [20], of an acrylic ester represented by general formula [22] to Diekman condensation reaction. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; and amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 25-100xc2x0 C., for a period of 30 minutes to 24 hours. If desired, the reaction may be carried out in an atmosphere of an inert gas such as argon or nitrogen.
The compound of general formula [2e] can be obtained by, for example, subjecting a compound of general formula [21] to a de-carboxylation reaction. The reagents used in this reaction are lithium chloride, lithium iodide, sodium chloride, pyridine and the like. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; water; acetic acid; and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 25xc2x0 C. to 250xc2x0 C. and preferably at 100-190xc2x0 C., for a period of 30 minutes to 24 hours.
Next, the processes for producing the compounds of the present invention will be explained.
In the production processes mentioned above, the compounds of general formulas [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [16], [17], [18], [19], [20], [21], [22], [24], [25], [26], [26a], [26b], [1a], [1b], [1c], [1f], [1g], [1i], [1k], [1l], [1la], [1m], [1ma], [1o], [1p], [1q], [1r], [2a], [2b], [2c], [2d] and [2e] can be put to use in the form of salts thereof, too. As salts thereof, the same salts as mentioned in the paragraph of the salts of compound of general formula [1] can be used.
In the production processes mentioned above, the compounds of general formulas [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [16], [17], [18], [19], [20], [21], [22], [24], [25], [26], [26a], [26b], [1a], [1b], [1c], [1f], [1g], [1i], [1k], [1l], [1la], [1m], [1ma], [1o], [1p], [1q], [1r], [2a], [2b], [2c], [2d] and [2e] can have isomers such as optical isomers, geometrical isomers and tautomers. In such cases, these isomers can also be used in the present invention. Further, solvated products, hydrates, and various crystal forms of these compounds can also be used. Further, in the compounds of [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [16], [17], [18], [19], [20], [21], [22], [24], [25], [26], [26a], [26b], [1a], [1b], [1c], [1f], [1g], [1i], [1k], [1l], [1la], [1m], [1ma], [1o], [1p], [1q], [1r], [2a], [2b], [2c], [2d] and [2e], some of the compounds can have an amino group, a hydroxyl group or a carboxyl group. It is also possible to protect these groups previously with conventional protecting groups and, after the reaction, to eliminate these protecting groups according to the methods known in themselves.
In cases where the compound of the present invention is a 1-thia-4,8-diazaspiro[4.5]decane derivative, such a compound can be synthesized according to the Production Processes 3 and 4 mentioned below, for example:
[Production Process 3]
[Production Process 4]
wherein R1h, R2, k and nxe2x80x2 are as defined above; R13a represents an unprotected or protected amino, alkylamino, arylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino or alkylsulfonylamino group; R represents a protecting group for carboxyl group; X represents a protecting group for amino group; and Z represents halogen atom, alkylsulfonyloxy group or arylsulfonyloxy group.
The compound of general formula [35] can be obtained by, for example, the process mentioned in Yakugaku Zasshi, Vol. 91, No, 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [32] with an amine represented by general formula [33] or an ammonium salt and a compound represented by general formula [34] in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the reaction product to a dehydrating ring closure.
As the amine represented by general formula [33] or the ammonium salt which can be used in this reaction, for example, primary amines such as methylamine, benzylamine, aniline, phenethylamine or the like, amino acids such as leucine, asparagine, aspartic acid, xcex2-alanine or the like, and ammonium salts such as ammonium carbonate, ammonium sulfate and the like can be referred to. The amine of general formula [33] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. The compound of general formula [34] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the dehydrating agent which can be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the-weight of the compound of general formula [32]. As the catalyst which can be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [32]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
It is also possible to obtain the compound of general formula [36] by de-protecting a compound of general formula [35] in the presence or absence of an acid or a base.
As the acid which may be used in this reaction according to the need, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [35]. As the base which may be used in this reaction according to the need, organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamine and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; and alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [35]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-110xc2x0 C. for a period of 30 minutes to 24 hours.
The compound of general formula [1s] is obtained by, for example, subjecting a compound of general formula [36] to an acylation reaction or sulfonylation reaction in the presence or absence of a base.
As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, 4-isopropylbenzoyl chloride, ethylsuccinyl chloride and the like can be referred to. As the sulfonylating agent, methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to. The amounts of said acylating agent and sulfonylating agent are 1-20 mol and preferably 2-6 mol per mol of the compound of general formula [36]. As the base which may be used according to the need, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 2-4 mol per mol of the compound of general formula [36]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [37] can be obtained by, for example, the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, pages 363-383 (1971). More concretely speaking, it can be obtained by reacting a compound of general formula [32] with an amine represented by general formula [33] or an ammonium salt and mercaptoacetic acid in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the product to a dehydrating ring closure.
As the amines represented by general formula [33] which can be used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine or the like and amino acids such as leucine, asparagine, aspartic acid, xcex2-alanine or the like can be referred to. As the ammonium salts, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine of general formula [33] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. The mercaptoacetic acid is used in amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the dehydrating agent which can be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [32]. As the catalyst which can be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [32]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
The compound of general formula [38] can be obtained by, for example, reacting a compound of general formula [37] with a compound of general formula [39] in the presence of a base. As the base used in this reaction, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-5 mol per mol of the compound of general formula [37]. The compound of general formula [39] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [37]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at xe2x88x9278xc2x0 C. to 150xc2x0 C. and preferably at xe2x88x9250xc2x0 C. to 120xc2x0 C., for a period of 30 minutes to 24 hours. If desired, the reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
It is also possible to obtain the compound of general formula [38] by the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [32] in the presence or absence of a dehydrating agent and/or a catalyst with an amine represented by general formula [33] or an ammonium salt and a compound represented by general formula [40] which can be synthesized according to the method mentioned in SYNTHETIC COMMUNICATIONS, Vol. 21, No. 2, Pages 249-263 (1991) or the like and subjecting the product to a dehydrating ring closure.
As the amine represented by general formula [33] used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine and the like and amino acids such as leucine, asparagine, aspartic acid, xcex2-alanine and the like can be referred to. As the ammonium salt, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine of general formula [33] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. The compound of general formula [40] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the dehydrating agent, for example, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the amount of the compound of general formula [32]. As the catalyst which can be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [32]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C. for a period of 30 minutes to 24 hours. If desired, the reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.
Further, it is also possible to obtain the compound of general formula [38] by subjecting a compound of general formula [35] to an esterification reaction.
This reaction may be a usual esterification reaction, such as a method via an acid chloride, a method via an acid anhydride, a method using a base and an alkyl halide, a method using a condensing agent and an additive, etc. In a case where a base and an alkyl halide are used, the base which can be used include organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc. The amount of the base is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [35]. As the alkyl halide which can be used in this reaction, methyl iodide, ethyl iodide, benzyl bromide and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [35]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200xc2x0 C. and preferably at 25-150xc2x0 C., for a period of 10 minutes to 24 hours. In a case where a condensing agent and an additive are used, the objective compound can be obtained by subjecting an alcohol such as ethanol, benzyl alcohol, tert-butanol or the like to a condensation reaction with a condensing agent and an additive. As the condensing agent used in this reaction, for example, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-Nxe2x80x2-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to. As the additive used in this reaction, for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The alcohol, condensing agent and additive used in this reaction are used each in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [35]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200xc2x0 C. and preferably at 25-150xc2x0 C., for a period of 10 minutes to 24 hours.
The compound of general formula [41] can be obtained by de-protecting a compound of general formula [38] in the presence or absence of an acid or a base.
As the acid which may be used in this reaction according to the need, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [38]. As the base which may be used in this reaction according to the need, organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; and alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like can be referred to, and the amount thereof is 1-50 mol and preferably 1-30 mol per mol of the compound of general formula [38].
In a case where X is a tert-butyloxycarbonyl group and R is an ethyl group, the acids which can be used are hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [38]. In a case where X is a 9-fluorenylmethoxycarbonyl group and R is a tert-butyl group, the bases which can be used are piperidine, morpholine, dimethylaminopyridine and the like, and the amount thereof is 1-30 mol and preferably 1-5 mol per mol of the compound of general formula [38]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-200xc2x0 C. and preferably at 20-70xc2x0 C. for a period of 10 minutes to 5 hours.
The compound of general formula [42] can be obtained by, for example, subjecting a compound of general formula [41] to an acylation reaction or a sulfonylation reaction in the presence or absence of a base.
As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, ethylsuccinyl chloride and the like can be referred to. As the sulfonylating agent, methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to. The amount of said acylating agent and sulfonylating agent is each 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [41]. As the base used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [41]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [42] can be obtained by, for example, subjecting a compound of general formula [41] to an alkylation reaction in the presence of a base. As the alkylating agent which can be used in this reaction, for example, methyl iodide, benzyl bromide and the like can be referred to, and the amount thereof is 1-20 mol and preferably 1-4 mol per mol of the compound of general formula [41]. As the base used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 2-20 mol and preferably 2-4 mol per mol of the compound of general formula [41]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200xc2x0 C. and preferably at 25-150xc2x0 C., for a period of 10 minutes to 24 hours.
The compound of general formula [42] can be obtained by, subjecting a compound of general formula [41] to a nitrosation reaction in the presence of a base and then reducing the product. The nitrosation reaction can be carried out according to the procedure mentioned in Organic Syntheses Collective Volume, Vol. 2, Page 211 (1943). As the nitrosating agent, for example, nitrous acid and the like can be used. The nitrosating agent is used in an amount of 1-10 mol and preferably 1-4 mol per mol of the compound of general formula [41]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200xc2x0 C. and preferably at 0-100xc2x0 C., for a period of 10 minutes to 24 hours.
The reduction as a subsequent step can be carried out according to the description of Organic Syntheses Collective Volume, Vol. 2., Page 211 (1943). That is, the objective product can be obtained by reacting the nitroso compound synthesized from the compound of general formula [41] with a reductant such as zinc powder. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and acetic acid. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200xc2x0 C. and preferably at 0-100xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1s] can be obtained by, for example, subjecting a compound of general formula [42] to a de-esterification reaction in the presence or absence of an acid or a base.
As the acid which can be used in this reaction according to the need, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to. The amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [42]. As the base used in this reaction according to the need, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [42]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; acetic acid; water; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150xc2x0 C. and preferably at 25-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1t] can be obtained by subjecting a compound of general formula [1s] to an amidation reaction.
This reaction may be a usual amidation reaction, such as a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. For example, in the case of using a base, a condensing agent and an additive, the amines which can be used in the reaction include primary amines such as methylamine, benzylamine, aniline, phenethylamine, aminothiazole and the like; secondary amines such as dimethylamine, diethylamine, di-n-propylamine and the like; cyclic amines such as piperidine, morpholine and the like; and amino acids such as leucine, asparagine, aspartic acid, xcex2-alanine and the like. The amine is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1s]. As the base which can be use in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1s]. As the condensing agent, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-Nxe2x80x2-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to, and as the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The amounts of the condensing agent and the additive are both 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1s]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve nd the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1u] can be obtained by, for example, oxidizing a compound of general formula [1s].
As the oxidant which can be used in this reaction, for example, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like; hydrogen peroxide; chromic acid; potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1s]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at a temperature ranging from 0xc2x0 C. to reflux temperature of the used solvent and preferably at 0-30xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1v] can be obtained by subjecting a compound of general formula [1u] to an amidation reaction. This reaction may be a usual amidation reaction, such as a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. For example, in the case of using a base, a condensing agent and an additive, the amines which can be used in the reaction include primary amines such as methylamine, benzylamine, aniline, phenethylamine, aminothiazole and the like; secondary amines such as dimethylamine, diethylamine, di-n-propylamine and the like; cyclic amines such as piperidine, morpholine and the like; and amitno acids such as leucine, asparagine, aspartic acid, xcex2-alanine and the like. The amine is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1u]. As the base which can be used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1u]. As the condensing agent, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-Nxe2x80x2-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to, and as the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The amounts of the condensing agent and the additive are both 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1u]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [1v] can be obtained by, for example, oxidizing a compound of general formula [1t].
As the oxidant which can be used in this reaction, for example, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like; hydrogen peroxide; chromic acid; potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1t]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at a temperature ranging from 0xc2x0 C. to reflux temperature of the used solvent and preferably at 0-30xc2x0 C., for a period of 30 minutes to 24 hours.
The compounds of general formulas [1s], [1t], [1u] and [1v] which have been obtained in the above-mentioned manner can be converted to other compounds of general formula [1] by, for example, subjecting them to reactions known in themselves such as oxidation, reduction, rearrangement, substitution, halogenation, dehydration, hydrolysis, etc. or appropriately combining these reactions. The compounds of general formula [1s], [1t], [1u] and [1v] or salts thereof thus obtained can be isolated and purified by the conventional procedures such as extraction, crystallization and/or column chromatography, etc.
By converting the compound of [1s] or [1u], for example, to an acid halide by the conventional method, reacting the acid halide with diethyl malonate and magnesium chloride in the presence of a base such as triethylamine and then subjecting the product to hydrolysis and decarboxylation, there can be obtained a compound in which R13a is an an unsubstituted or substituted alkyl group. By converting the compound of [1s] or [1u] to an acid halide by the conventional method and then reacting the acid halide with alkylmercaptan, there can be obtained a compound in which R13a is an unsubstituted or substituted alkylthio group. Further, by converting the compound of [1s] or [1u] to an acid halide by the conventional method and then subjecting the acid halide to Friedel-Crafts reaction with an aryl or heterocyclic group in the presence of an acid such as aluminum chloride or the like, there can be obtained a compound in which R13a is an unsubstituted or substituted aryl or heterocyclic group.
The compound of general formula [32] which is a starting compound for production of the compound of the present invention can be produced according to the method described in, for example, Synthesis, Page 48 (1986) or the like or a similar method.
In the production processes mentioned above, the compounds of general formulas [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [1s], [1t] and [1u] can be used in the form of a salt, too. As said salt, the same ones as mentioned in the paragraph of salts of the compound of general formula [1] can be referred to.
The compounds of general formulas [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [1s], [1t], [1u] and [1v] can be converted to salts thereof. As said salts, the same ones as mentioned in the paragraph of general formula [1] can be referred to.
In the above-mentioned production processes, some of the compounds of general formulas [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [1s], [1t] and [1u] have isomers such as optical isomer, geometrical isomer, tautomer, etc. In such cases, these isomers are also usable in the present invention. Further, solvated products, hydrates and various crystal forms of these compounds are also usable. In the compounds of general formulas [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [1s], [1t], [1u] and [1v], some compounds have an amino group, a hydroxyl group, a mercapto group or a carboxyl group. It is possible, if desired, to protect these groups previously with a usual protecting group and, after the reaction, to eliminate the protecting group according to a method known in itself.
It is also possible to obtain the compounds of general formulas [1w], [1x] and [1y] by, for example, the following Production Processes 5-7.
Production Process 5 
wherein
Y4 represents O or NH; q reprsesents 0, 1, 2 or 3, provided that when q is zero, Y4 represents NH; E4 represents amino acid residue; and R1hxe2x80x2 represents a roup of the following general formula:
R15xe2x80x2xe2x80x94Y3xe2x80x2xe2x80x94
wherein Y3xe2x80x2 represents carbonyl group; and R15xe2x80x2 represents hydrogen atom, cyano group, protected carboxyl, hydroxyl or mercapto group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamoyl, carbamoyloxy or heterocyclic group; or a group of the following general formula:
R16xe2x80x94(E3)sxe2x80x94
wherein R16 represents hydrogen atom or a protecting group for amino group; E3 represents amino acid residue; and s represents 2 or 3; and X represents a protecting group for amino group; and R2xe2x80x2 represents hydrogen atom or an unsubstituted or substituted acyl group.
The amino acid-bounded resin of general formula [44] can be obtained by reacting a resin of general formula [43] with an amino acid derivative, followed by de-protection. As the resin usable in this reaction, the resins conventionally used in the solid phase method can be referred to, of which examples include benzhydrylamine resin, 4-methylbenzhydrylamine resin, Rink amide resin, oxymethyl resin, oxymethylphenoxymethyl resin and the like. As the amino acid derivatives usable in this reaction, there can be referred to those amino acid derivatives in which t-butyloxycarbonyl (Boc) group or 9-fluorenylmethoxycarbonyl (Fmoc) group is used as protecting group for an xcex1-amino acid, those in which t-butyl ester group, benzyl ester group, cyclohexyl ester group or the like is used as protecting group for the side chain functional group such as the side chain carboxyl group of aspartic acid or glutamic acid; those in which t-butyl group, benzyl group, 2,6-dibromobenzyl group or the like is used as a protecting group for the side chain hydroxyl group of serine, threonine, tyrosine; those in which trityl group, acetamidomethyl group, t-butyl group or the like is used as a protecting group for the side chain thiol group of cycteine; etc. Among these amino acid derivatives, Fmoc-amino acids are preferred.
(1) An amino acid-bounded resin with protected N-terminal can be obtained by condensing a resin with an amino acid derivative. Concretely speaking, it can be obtained by introducing a resin into a reactor, adding a solvent thereto to swell the resin, filtering off the solvent, adding an amino acid derivative and a condensation reagent, again adding a solvent, and then carrying out a reaction. As the condensation reagent used in this reaction, dicyclohexyl carbodiimide, diisopropyl carbodiimide, benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) and the like can be referred to, and the amount thereof is 1-10 equivalents per equivalent of amino group in the resin. In the case of using PyBOP or PyBroP, an amine such as diisopropylethylamine, triethylamine or the like may be added, if desired, in an amount of 1-5 equivalents per equivalent of the condensing agent. It is also allowable to add 0.5-5 equivalents of an ester-activator such as N-hydroxybenzotriazole, N-hydroxy-7-azabenzotriazole or the like per equivalent of the condensation reagent. As the solvents used in this reaction, N,N-dimethylformamide, dichloromethane, chloroform, N-methylpyrrolidone and the like can be referred to. Although the amount of the solvent is not particularly critical, 5-100 ml and preferably 5-20 ml of solvent is used per gram of the resin when used for swelling the resin, and 5-100 ml, preferably 5-50 ml, of solvent is used per gram of the resin when used for reaction. This reaction is carried out usually at 10-40xc2x0 C. and preferably at 20-30xc2x0 C. for a period of 5-120 minutes.
(2) An amino acid-bounded resin with de-protected N-terminal can be obtained by reacting an amino acid-bounded resin having a protected N-terminal with a de-protecting agent and thereby eliminating the protecting group for a-amino acid. Concretely speaking, a peptide-bonding resin having a protected N-terminal is reacted in the presence of an acid or a base in the resence or absence of a solvent. The de-protecting group used in this reaction is properly selected in accordance with the kind of protecting group for xcex1-amino acid. For example, in the case where the protecting group for xcex1-amino acid to be eliminated is a Boc group, an acid such as trifluoroacetic acid, methanesulfonic acid and the like is used. In the case where the protecting group for xcex1-amino acid to be eliminated is a Fmoc group, a base such as piperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene or the like is used. The solvent used in this reaction is not critical so far as the solvent exercises no adverse influence on the reaction. When an acid is used for the elimination, dichloromethane, dichloroethane and the like can be used. When a base is used for the elimination, N,N-dimethylformamide, N-methylpyrrolidone and the like can be used. When a solvent is used, the solvent may be used in a proportion of 5-20 ml per one gram of the resin. The reaction is carried out usually at 10-40xc2x0 C. and preferably at 20-30xc2x0 C. for a period of 5-120 minutes.
For combining two or more amino acid residues, the procedure mentioned above is repeated.
The resin of general formula [45] can be obtained by reacting an amino acid-bounded resin of general formula [44] with a compound of general formula [47], followed by de-protection. This reaction can be effected in the same manner as above.
The resin of general formula [46] can be btained by acylating a resin of general formula [45]. This reaction can be effected in the same manner as above. In a case where the functional group of the compound bonded to the resin of formula [46] is protected, conversion to other compound can be carried out by de-protection followed by acylation, sulfonylation or the like. These reactions may be effected in the same manner as above.
The compound of general formula [1w] can be obtained by treating a resin of general formula [46] in the presence of an acid to remove the resin therefrom. The acid used in this reaction is properly selected in accordance with the combination of the used resin and the protecting group for amino group. The acids include, for example, trifluoromethanesulfonic acid, anhydrous hydrogen fluoride, trifluoroacetic acid and the like. The solvent used in this reaction is not critical so far as the solvent exercises no adverse influence on the reaction. For example, dichloromethane is used for this purpose. Although the amount of the solvent is not critical, 5-100 ml of the solvent may be used per gram of the resin. The reaction is carried out at xe2x88x9210xc2x0 C. to 40xc2x0 C. and preferably at 0-20xc2x0 C., for a period of 30-300 minutes.
Production Process 6 
wherein
Y5 represents O or NH; q represents 0, 1, 2 or 3; E2 represents amino acid residue; k represents 1, 2 or 3; and R1hxe2x80x2 represents a group of the following formula:
R11xe2x80x2xe2x80x94Y2xe2x80x2xe2x80x94
wherein Y2xe2x80x2 represents carbonyl group; and R11xe2x80x2 represents hydrogen atom, cyano group, protected carboxyl, hydroxyl or mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamolyl, carbamoyloxy or heterocyclic group; or a group of the following general formula:
R12xe2x80x94(E1)jxe2x80x94
wherein R12 represents hydrogen atom or a protecting group for amino group; R14 represents hydroxyl group or amino group; E1 represents amino acid residue; and j represents 2 or 3; and X represents a protecting group for amino group; and R2xe2x80x2 represents hydrogen atom or an unsubstituted or substituted acyl group.
The resin of general formula [48] can be obtained by reacting a resin of general formula [44a] with a compound of general formula [50], followed by de-protection. This reaction may be carried out in the same manner as mentioned in the paragraph of Production Process 5.
The resin of general formula [49] can be obtained by acylating a resin of the general formula [48]. This reaction may be carried out in the same manner as above. In a case where the functional group of the compound bonded to the resin of formula [48] is protected, conversion to other compound can be carried out by de-protection, followed by acylation, sulfonylation or the like. These reaction may be carried out in the same manner as above.
The compound of the general formula [1x] can be obtained by treating a resin of general formula [49] in the presence of an acid to remove the resin therefrom. This reaction may be carried out in the same manner as mentioned in the paragraph of Production Process 5.
Production Process 7 
wherein
Y5 represents O or NH; k represents 1, 2, or 3; q represents 0, 1, 2 or 3; u represents 0, 1, 2 or 3; and R1hxe2x80x2 represents a group of the following general formula:
R11xe2x80x2xe2x80x94Y2xe2x80x2xe2x80x94
wherein Y2xe2x80x2 represents carbonyl group; and R11xe2x80x2 represents hydrogen atom, cyano group, protected carboxyl, hydroxyl or mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamoyl, carbamoyloxy or heterocyclic group; or a group of the following general formula:
R12xe2x80x94(E1)jxe2x80x94
wherein R12 represents hydrogen atom or a protecting group for amino group; E1 represents amino acid residue; and j represents 2 or 3; and R2xe2x80x2 represents hydrogen atom, or an unsubstituted or substituted acyl group; R14 represents hydroxyl group or amino group; E2 and E5 each represents amino acid residue; and X represents a protecting group for amino group.
The resin of general formula [51] can be obtained by reacting a resin of general formula [44b] with a compound of general formula [53], followed by de-protection. This reaction may be carried out in the same manner as in the description of Production Process 5.
The resin of general formula [52] can be obtained by acylating a resin of general formula [51]. This reaction may be carried out in the same manner as above. In a case where the functional group of the compound bonded to the resin of formula [52] is protected, conversion to other compounds can be carried out by de-protection, followed by acylation, sulfonylation, etc. These reactions may be carried out in the same manner as above.
The compound of general formula [1y] can be obtained by treating a resin of general formula [52] in the presence of an acid to remove the resin therefrom. This reaction may be carried out in the same manner as mentioned in the paragraph of Production Process 5.
The compound of general formula [55] which is a starting compound for production of the compound of the present invention can be obtained, for example, in the following manner.
[Production Process F]
wherein X represents a protecting group for amino group; R3xe2x80x2, R4xe2x80x2, R5 and R6 are as defined above; and R2xe2x80x2 represents an unsubstituted or substituted acyl group.
The compound of general formula [54] can be obtained according to, for example, the process mentioned in JP-A 53-44574, or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [32] with a compound of general formula [8a] in the presence or absence of a base, a dehydrating agent and a catalyst, and subjecting the product to a dehydrating ring closure. Although the compound of general formula [8a] used in this reaction is not particularly critical, D-cysteine, L-cysteine, D-penicillamine and L-penicillamine and salts thereof can be referred to, for example. The compound of general formula [8a] is used in an amount of 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the base which may be used according to the need, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like, alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc. can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the dehydrating agent which may be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [32]. As the catalyst which may be used according to the need, paratoluene-sulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-1 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [32]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150xc2x0 C. and preferably at 20-120xc2x0 C., for a period of 30 minutes to 24 hours.
The compound of general formula [55] can be obtained by, for example, acylating a compound of general formula [54] in the presence or absence of a base. As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, pyrrolecarbonyl chloride, thiazolecarbonyl chloride and the like can be referred to. The amount of said acylating agent is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [54]. As the base which may be used according to the need, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [54]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C. and preferably at 0-120xc2x0 C., for a period of 30 minutes to 24 hours.
It is also possible, if desired, to eliminate the protecting group just after the compound [55] has been obtained and thereafter to convert it to other protecting group.
In the production processes mentioned above, the compounds of general formulas [8a], [32], [43], [44], [44a], [44b], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [1w], [1x] and [1y] can be used in the form of a salt, too. As said salt, the same ones as mentioned in the paragraph of salts of the compound of general formula [1] can be referred.
In the above-mentioned Production Processes 5, 6, 7 and F, some of the compounds of general formulas [8a], [32], [43], [44], [44a], [44b], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [1w], [1x] and [1y] have isomers such as optical isomer, geometrical isomer, tautomer, etc. In such cases, these isomers are also usable in the present invention. Further, solvated products, hydrates and various crystal forms of these compounds are also usable.
In the compounds of general formulas [8a], [32], [43], [44], [44a], [44b], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [1w], [1x] and [1y], some compounds have an amino group, a hydroxyl group, a mercapto group or a carboxyl group. It is possible, if desired, to protect these groups with a usual protecting group previously and, after the reaction, to eliminate the protecting group according to a method known in itself.
When the compound of the present invention is used as a medical drug, conventional adjuvants for preparations such as an excipient, a carrier, a diluent and the like may be appropriately mixed into the composition, and the preparations thus obtained can be orally or non-orally administered in the form of tablet, capsule, powder, syrup, granule, pill, suspension, emulsion, solution, powdery preparation, suppository, ointment, injection and the like according to usual ways. The method, dosage and frequency of administration can properly be selected according to age, body weight and symptom of the patient. Usually, in case of adult patients, the preparation is orally or non-orally (for example, by injection, instillation, rectal application and the like) administered at a dosage of 0.1 to 100 mg/kg per day, at once or in several portions.
Next, pharmacological activities of typical compounds of the present invention will be mentioned below.
[Testing Method]
Test Example 1: Preparation of Transfectant
A reporter plasmid was prepared according to the method of R. I. Scheinman et al. [Mol. Cell. Biol., Vol. 15, Pages 943-953 (1995)]. That is, a plasmid p(TRE)5TK-Luc was constructed by connecting a promoter of thymidine kinase (TK) at an upstream site of luciferase (Luc) gene which is a reporter gene and a 5-times repeated TRE sequence at a further upstream site thereof. The plasmid was co-transfected simultaneously with p3xe2x80x2SS plasmid (prepared by Stratagene Co.) by the electrotranspolation method onto mouse 3T3 fibroblast (ATCC: CCL-163) cultured in a Dulbecco""s modified Eagle""s medium (DMEM) containing 10% fetal calf serum (FCS). Then the cells were cultured in DMEM containing 10% FCS and 100 xcexcg/ml of Hygromycin B. Using the expression of Hygromycin-resistant gene contained in p3xe2x80x2SS as an indicator, cell strains of the transfectant into which the objective plasmid had been introduced stably were selected. Furthermore in the test mentioned below, cell strains showing expression of Luc gene under stimulation of 12-O-tetradecanoylphorbol 13-acetate (TPA, prepared by Sigma Co.) were used, and DMEM containing 10% FCS and 100 xcexcg/ml of Hygromycin B was used for the culture of cells.
Test Example 2: Luciferase Assay
The cells prepared above were suspended in culture medium, and plated 96 well-plate at 1xc3x97104 cells/0.1 ml. After culturing it overnight, 50 xcexcl of test compounds solution and 40 xcexcl of culture medium were added, and incubated. After one hour 10 xcexcl of 200 ng/ml TPA solution was added and the culture was continued for an additional 16 hours to stimulate the cells. The end of cluture, the cells were recovered, and cell lysis solutions were obtained. The Luc activity of the cell lysates was measured with a chemilluminescent detection kit (Pica Gene; manufactured by Toyo Ink Co.). The suppressive effect of each test compound could be assessed as a decrease of Luc activity, and the inhibition rate (%) was calculated according to the following formula:
Inhibition rate (%)=(1xe2x88x92Luc activity of cells to which the compound is added/Luc activity of cells to which the compound is not added)xc3x97100
Test Example 3: XTT Assay (Cytotoxicity Test)
The same culture plate as above was prepared, and test compound and TPA were added under the same conditions as above, after which a culture was carried out for 16 hours. The end of cluture, XTT reagent prepared according to the method of D. A. Scudievo [Cancer Res., Vol. 48, Pages 4827-4833 (1988)] was added and made to react for a prescribed period of time. Then, the amount of formazan formed by alive cells was analyzed by measuring absorbance at 450 nm using a micro plate reader. In this test, a decrease in absorbance is observed when the test compounds show a cytotoxicitic or a growth inhibitory activity. Cell viability (T/C %) was determined according to the following formula:
Cell Viability Rate (T/C %)=(Absorbance of well to which compound is added/Absorbance of well to which the compound was not added)xc3x97100
The results are shown in Table 52.
The compounds of Example No. 1, 6(3), 6(5), 13, 15, 17, 18(1), 18(8), 20(1) and 20(2) were converted to sodium salts according to the method of Example 42, and then used for the assay.
Test Example 4: Type II Collagen-induced Arthritis in Mice
The compound of Example 20 (1) was tested for the effect on type II collagen-induced arthritis, using 8 weeks old, male DBA/1J mice (Japan Charles River). Emulsion was prepared by mixing an equal volume of bovine type II collagen (prepared by Koken) in 0.1N acetic acid (2 mg/ml) and Freund""s complete adjuvant (prepared by Nacalai Tesque). Arthritis was induced by intradermal injection of 0.2 ml (the quantity of antigen: 200 xcexcg/head) of the emulsion into the skin of the tail root twice (day 0 and day 21). The test compound was suspended in 0.5% solution of methyl cellulose, and 100 mg/kg was orally administered once every day from day 21 to day 35. To the control group (negative control group), 0.5% methyl cellulose solution was administered in the same manner as above. Severity of the arthritis was scored 0: no change, 1: only one or two swelling of the joints or slight swelling of the ankle or toes, 2: swelling and/or rubor in further joints, 3: extensive swelling of whole paw, and the maximum possible score for arthritis was 12 points. As to the severity of destruction of joints and bones, X ray photographs of four paws were taken (Softex), and severity of destruction in the second to fifth articulationes interphalangeae, first to fifth articulationes metacarpophalangeae and metatarsophalangeae, and calcaneus was scored by 0 or 1 in accordance with presence or absence of destruction, and the severity of destruction in the carpus and tarsal was scored by 0 to 3. Overall severity of destruction of joints and bones was evaluated by a joint-bone destruction score, taking the total score of the four paws as 50 points [Method in Enzymology, 162, 361-373 (1988)].
The results are shown in Table 53, wherein the scores are mean values.